Dysregulation of autophagy in melanocytes contributes to hypopigmented macules in tuberous sclerosis complex

Yang, Fei; Yang, Lingli; Wataya‐Kaneda, Mari; Hasegawa, Junya; Tanemura, Atsushi; Tsuruta, Daisuke; Katayama, Ichiro

doi:10.1016/j.jdermsci.2017.11.002

Cited by 22 publications

(17 citation statements)

References 52 publications

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“…The mTORC1 signaling was defined to control the transcription of melanogenic enzymes and melanosome maturation [ 26 ]. Histochemical examination of hypomelanotic macules of TSC patients revealed that melanocytes were present but the number of melanin granules per melanocyte decreased in TSC-related hypomelanotic macules and that sirolimus increased the volume and number of melanin granules thorough autophagy and ER stress [ 27 – 29 ]. The results from this study are in line with these findings.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial

Wataya‐Kaneda

Nagai

Ohno

et al. 2020

Dermatol Ther (Heidelb)

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Introduction Our previous clinical studies have demonstrated the short-term efficacy and safety of the sirolimus gel for patients with tuberous sclerosis complex (TSC). However, long-term clinical evidence is lacking. Our objective was to assess the safety and efficacy of long-term treatment with the sirolimus gel for the skin lesions of TSC patients. Methods We conducted a multicenter, open-label, uncontrolled clinical trial in 94 Japanese patients with TSC. Patients applied the 0.2% sirolimus gel on their face or head twice daily for > 52 weeks (maximum 136 weeks for safety). The safety endpoints were the rate of adverse event (AE)-caused discontinuation (primary endpoint) and the incidence of AEs. The efficacy endpoint was the response rate of angiofibromas, cephalic plaques, and hypomelanotic macules. Results Among 94 enrolled patients (mean age, 21 years; range 3–53 years), the rate of AE-caused discontinuation was 2.1% (2/94 patients). Although application site irritation and dry skin occurred relatively frequently, none of the drug-related AEs were serious; most of the drug-related AEs resolved rapidly. The major drug-related AEs (≥ 5% in incidence) were application site irritation (30.9%), dry skin (27.7%), acne (20.2%), eye irritation (8.5%), pruritus (8.5%), erythema (7.4%), dermatitis acneiform (6.4%), and dermatitis contact (5.3%). The response rates of angiofibromas, cephalic plaques, and hypomelanotic macules were 78.2% [95% confidence interval (CI) 68.0–86.3%], 66.7% (95% CI 51.1–80.0%), and 72.2% (95% CI 46.5–90.3%), respectively. Conclusions The gel was well tolerated for a long time by patients with TSC involving facial skin lesions and continued to be effective. Trial Registration ClinicalTrials.gov identifier: NCT02634931.

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Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial

Wataya‐Kaneda

Nagai

Ohno

et al. 2020

Dermatol Ther (Heidelb)

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“…The autophagy deficient melanocytes displayed a senescence associated secretory phenotype (SASP) (Ni et al, 2016). This low-grade inflammation is typical for senescent cells, and melanocyte SASP is implicated in the pathogenesis of vitiligo (Bellei et al, 2013; Qiao et al, 2016) and hypopigmented macules in tuberous sclerosis complex (Yang et al, 2018).…”

Section: Autophagy In Epithelial Cells Of the Skinmentioning

confidence: 99%

Autophagic Control of Skin Aging

Eckhart

Tschachler

Грубер

2019

Front. Cell Dev. Biol.

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The skin forms the barrier to the environment. Maintenance of this barrier during aging requires orchestrated responses to variable types of stress, the continuous renewal of the epithelial compartment, and the homeostasis of long-lived cell types. Recent experimental evidence suggests that autophagy is critically involved in skin homeostasis and skin aging is associated with and partially caused by defects of autophagy. In the outer skin epithelium, autophagy is constitutively active during cornification of keratinocytes and increases the resistance to environmental stress. Experimental suppression of autophagy in the absence of stress is tolerated by the rapidly renewing epidermal epithelium, whereas long-lived skin cells such as melanocytes, Merkel cells and secretory cells of sweat glands depend on autophagy for cellular homeostasis and normal execution of their functions during aging. Yet other important roles of autophagy have been identified in the dermis where senescence of mesenchymal cells and alterations of the extracellular matrix (ECM) are hallmarks of aging. Here, we review the evidence for cell type-specific roles of autophagy in the skin and their differential contributions to aging.

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“…Tuberous sclerosis complex (TSC) gene mutations result in a broad range of symptoms, including hypopigmented macules as the earliest sign. MCs from patients with TSC displayed autophagic dysregulation and depigmentation in TSC2‐KD MCs can be accelerated by inhibiting autophagy and completely reversed by induction of autophagy (F. Yang et al., 2018).…”

Section: Conventional Forms Of Cell Death In Vitiligomentioning

confidence: 99%

The fate of melanocyte: Mechanisms of cell death in vitiligo

Yang

Xiang

et al. 2021

Pigment Cell Melanoma Res

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Loss of melanocytes (MCs) is the most notable feature of vitiligo. Hence, it is critical to clarify the mechanisms of MC destruction in vitiligo. Apoptosis is most widely studied cell death pathways in vitiligo. In addition, the other two forms of cell death, conventional necrosis and autophagy seem to be involved in the death of vitiligo MCs under certain situations. Moreover, new types of regulated cell death including necroptosis, pyroptosis, and ferroptosis may also participate in the pathogenesis of vitiligo. Anoikis is likely to be connected with the death of detached MCs, which is provoked specifically by loss of anchorage. Primary phagocytosis, later called phagoptosis can execute death of viable cells, probably partly responsible for the loss of MCs in vitiligo. In this review, we aim to summarize the latest insights into various forms of MC death in vitiligo and discuss the corresponding mechanisms.

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Dysregulation of autophagy in melanocytes contributes to hypopigmented macules in tuberous sclerosis complex

Abstract: Our data demonstrate that melanocytes of patients with TSC display autophagic dysregulation, which thereby reduced pigmentation, serving as the basis for the hypomelanotic macules characteristic of TSC.

Cited by 22 publications

References 52 publications

Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial

Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial

Autophagic Control of Skin Aging

The fate of melanocyte: Mechanisms of cell death in vitiligo

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